Skin cancer is the most common neoplasm in the United States with a lifetime risk equal to that of all other cancers combined. Like other cancers, skin cancers arise via the accumulative acquisition of discrete cooperating genetic events. The purpose of this proposal is to dissect the molecular mechanisms that mediate the roles of oncogenes and tumor suppressor genes in skin carcinogenesis. Based on previous studies and new preliminary data, the following is proposed: 1) Missense mutations in the p53 tumor suppressor gene, such as p53R172H (equivalent to the human p53R172H "hot spot" mutation), exhibit a gain-of-function activity resulting in an increased susceptibility to skin cancer and accelerated tumor progression. 2) Centrosome amplification induced by elevated levels of Aurora-2 kinase contributes to the accelerated tumor progression observed in mice expressing a p53R172H allele in the epidermis. 3) Deregulated expression of the p53 homologue, p63, promotes skin carcinogenesis through its ability to induce proliferation and inhibit terminal differentiation. 4) Deregulated expression of c-Myc influences both tumor susceptibility and tumor phenotype by inducing proliferation of stem cells and by altering their cell fate, and deregulated expression of bcl-xL, an inhibitor of apoptosis, may further augment the oncogenic effect of c-Myc. These hypotheses will be tested using inducible mouse models that allow the activation of oncogenes or the inactivation of tumor suppressor genes in a restricted area of the skin in stem cells that renew the epidermis and its appendages. This approach allows the generation of mice with genetic changes that closely mimic the sporadic focal accumulation of somatic mutations in human tumors. The tumors that develop in these inducible mouse models will be a valuable resource, since they arise as a result of discrete genetic events and progress to metastases by mechanisms that are dependent on and independent of genetic instability. Thus, these tumors will be analyzed with Affymetrix and BAC/CGH arrays to identify novel genetic changes associated with tumor progression. The development of transgenic/knockout mouse models with defined genetic alterations, which have been implicated in causing human skin cancer, will have a major impact on the development of novel therapeutic approaches in the future.